Circulating extracellular DNA is an independent predictor of mortality in elderly patients with venous thromboembolism

Jiménez-Alcázar, Miguel; Limacher, Andreas; Panda, Rachita; Méan, Marie; Bitterling, Josephine; Peine, Sven; Renné, Thomas; Beer, Jürg H.; Aujesky, Drahomir; Lämmle, Bernhard; Fuchs, Tobias A.

doi:10.1371/journal.pone.0191150

Cited by 32 publications

(29 citation statements)

References 33 publications

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“…Plasma DNA levels are elevated in patients with DVT correlating with C-reactive protein, D-dimer, von Willebrand factor, and MPO 132 . Moreover, in elderly patients, levels of circulating extracellular DNA correlated with the extent of venous thromboembolism, inflammation as assessed by C-reactive protein and leukocytosis, and predicted mortality 133 . Recently, flow cytometric detection of MPO/citrullinated histone 3-positive neutrophils and serum dsDNA have been proposed for biomarker assessment 30 .…”

Section: Nets In Venous Thrombosis and Thromboembolismmentioning

confidence: 94%

In vivo evidence for extracellular DNA trap formation

et al. 2020

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Extracellular DNA trap formation is a cellular function of neutrophils, eosinophils, and basophils that facilitates the immobilization and killing of invading microorganisms in the extracellular milieu. To form extracellular traps, granulocytes release a scaffold consisting of mitochondrial DNA in association with granule proteins. As we understand more about the molecular mechanism for the formation of extracellular DNA traps, the in vivo function of this phenomenon under pathological conditions remains an enigma. In this article, we critically review the literature to summarize the evidence for extracellular DNA trap formation under in vivo conditions. Extracellular DNA traps have not only been detected in infectious diseases but also in chronic inflammatory diseases, as well as in cancer. While on the one hand, extracellular DNA traps clearly exhibit an important function in host defense, it appears that they can also contribute to the maintenance of inflammation and metastasis, suggesting that they may represent an interesting drug target for such pathological conditions. Facts •The demonstration of extracellular DNA traps in vivo requires sections of affected tissues, which are to be investigated with special staining techniques. These structures are seen in multiple inflammatory and cancer diseases.Is there a simple biomarker that reflects extracellular DNA trap formation?• What is the contribution of extracellular microbe killing compared to intracellular killing following phagocytosis?• The mechanism of DNA trap formation is unknown.

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Section: Nets In Venous Thrombosis and Thromboembolismmentioning

confidence: 94%

In vivo evidence for extracellular DNA trap formation

et al. 2020

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“…In specimens obtained from humans, NETs are observed primarily in DVTs and pulmonary emboli in their organizing stage, where layers of neutrophils and platelets are present (50). Plasma DNA and biomarkers of NETs are elevated in patients with DVT (51)(52)(53). PAD4 is released with NETs, where it remains active (54), thus enabling it to citrullinate plasma proteins and change their behavior.…”

Section: Thrombosis and Cardiovascular Diseasementioning

confidence: 99%

Peptidylarginine deiminase 4: a nuclear button triggering neutrophil extracellular traps in inflammatory diseases and aging

2018

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Peptidylarginine deiminase 4 (PAD4) is a nuclear citrullinating enzyme that is critically involved in the release of decondensed chromatin from neutrophils as neutrophil extracellular traps (NETs). NETs, together with fibrin, are implicated in host defense against pathogens; however, the formation of NETs (NETosis) has injurious effects that may outweigh their protective role. For example, PAD4 activity produces citrullinated neoantigens that promote autoimmune diseases, such as rheumatoid arthritis, to which PAD4 is genetically linked and where NETosis is prominent. NETs are also generated in basic sterile inflammatory responses that are induced by many inflammatory stimuli, including cytokines, hypoxia, and activated platelets. Mice that lack PAD4-deficient in NETosis-serve as an excellent tool with which to study the importance of NETs in disease models. In recent years, animal and human studies have demonstrated that NETs contribute to the etiology and propagation of many common noninfectious diseases, the focus of our review. We will discuss the role of NETs in thrombotic and cardiovascular disease, the induction of NETs by cancers and its implications for cancer progression and cancer-associated thrombosis, and elevated NETosis in diabetes and its negative impact on wound healing, and will propose a link between PAD4/NETs and age-related organ fibrosis. We identify unresolved issues and new research directions.-Wong, S. L., Wagner, D. D. Peptidylarginine deiminase 4: a nuclear button triggering neutrophil extracellular traps in inflammatory diseases and aging.

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“…It is considered as one of the prominent clinical biomarkers for thrombosis. The NET formation releases cell-free DNA into blood and tissue, which can be measured in plasma/serum (16). Our study demonstrates that collagen-epinephrine-treated mice significantly induced the release of extracellular DNA and ATP content, however, inhibition of ASK1 remarkably reduced both extracellular DNA and ATP content in mice plasma (Online Supplementary Figure S9A, Figure 3E).…”

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confidence: 77%